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Exome sequencing identifies recurrent somatic MAP2K1 and MAP2K2 mutations in melanoma

Abstract

We performed exome sequencing to detect somatic mutations in protein-coding regions in seven melanoma cell lines and donor-matched germline cells. All melanoma samples had high numbers of somatic mutations, which showed the hallmark of UV-induced DNA repair. Such a hallmark was absent in tumor sample–specific mutations in two metastases derived from the same individual. Two melanomas with non-canonical BRAF mutations harbored gain-of-function MAP2K1 and MAP2K2 (MEK1 and MEK2, respectively) mutations, resulting in constitutive ERK phosphorylation and higher resistance to MEK inhibitors. Screening a larger cohort of individuals with melanoma revealed the presence of recurring somatic MAP2K1 and MAP2K2 mutations, which occurred at an overall frequency of 8%. Furthermore, missense and nonsense somatic mutations were frequently found in three candidate melanoma genes, FAT4, LRP1B and DSC1.

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Figure 1: Coding somatic single-nucleotide substitutions in seven melanoma samples.
Figure 2: Main pathways affected in seven melanoma samples.
Figure 3: Circos representation of selected chromosomes.
Figure 4: Functional characterization and in silico modeling of the p.

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Acknowledgements

We thank F. Schütz and P. Bady for statistical discussions, P. Descombes for high-throughput sequencing, D. Martinet for aCGH data and C. Rivolta for valuable comments on the manuscript. We thank A. Simpson and R. Strausberg for their constant support. Part of the computation was performed on the cluster at the Vital-IT computing center. This work was supported by the Ludwig Institute for Cancer Research (C.I. and S.E.A.), the Hilton-Ludwig Cancer Metastasis Initiative, funded by the Conrad N. Hilton Foundation (D.R.), the Swiss National Science Foundation (SNF) National Centres of Competence in Research (NCCR) Frontiers in Genetics (S.E.A.) and the European Research Council (ERC; S.E.A.).

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S.I.N., C.I., A.V., D. Rimoldi, B.J.S., C.V.J., J.S.B., T.D.H. and S.E.A. designed experiments and wrote the manuscript. A.V., B.J.S. and C.I. performed statistical analysis. D. Rimoldi and K.M. established cell lines, prepared samples and performed functional studies. S.I.N., C.G., M.G. and K.H. performed exome sequencing and validations. S.I.N., C.I., A.V., B.J.S., D. Robyr, D. Rimoldi O.B., I.X. and S.E.A. analyzed the results. V.Z. and O.M. performed in silico modeling. D.S. and O.M. procured subject material. All authors commented on the manuscript.

Corresponding authors

Correspondence to Sergey I Nikolaev or Donata Rimoldi or Stylianos E Antonarakis.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–10 and Supplementary Tables 2, 3 and 5–8. (PDF 832 kb)

Supplementary Table 1

List of all somatic mutations in the studied melanomas (Excel) (XLSX 338 kb)

Supplementary Table 4

Copy number of genes from aCGH and SNP arrays and transcript expression (Excel) (XLS 54 kb)

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Nikolaev, S., Rimoldi, D., Iseli, C. et al. Exome sequencing identifies recurrent somatic MAP2K1 and MAP2K2 mutations in melanoma. Nat Genet 44, 133–139 (2012). https://doi.org/10.1038/ng.1026

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